Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
Diabetes as a Global Health Problem (1-5):
Diabetes is the world's fastest growing chronic disease. On 20 Dec. 2006 the United Nation General Assembly passed United Nation Resolution 61/225 recognizing diabetes as a major health crisis facing all nations of the world. The Resolution designates 14 November each year as the United Nations “WORLD DIABETES DAY” and calls on all nations to develop national policies for the prevention, treatment and care of people living with diabetes and those at risk of developing diabetes.
In 2007, the five countries with the largest numbers of people with diabetes are India (40.9 million), China (39.8 million), the United States (19.2 million), Russia (9.6 million) and Germany (7.4 million). Each year a further 7 million people develop diabetes. Each year 3.8 million deaths are attributable to diabetes. An even greater number die from cardiovascular disease made worse by diabetes-related lipid disorders and hypertension. On average, people with T2DM will die 5-10 years before people without diabetes, mostly due to cardiovascular disease. Cardiovascular disease is the major cause of death in diabetes, accounting for some 50% of all diabetes fatalities, and much disability. People with T2DM are over twice as likely to have a heart attack or stroke as people who do not have diabetes. Indeed, people with T2DM are as likely to suffer a heart attack as people without diabetes who have already had a heart attack.
At least 50% of all people with T2DM are unaware of their condition. In some countries this figure may reach 80%. Up to 60% of T2DM is preventable by adopting a healthy diet and increasing physical activity.
T2DM is the largest cause of kidney failure in developed countries and is responsible for huge dialysis costs. T2DM has become the most frequent condition in people with kidney failure in countries of the Western world. 10% to 20% of people with diabetes will die of renal failure.
It is estimated that more than 2.5 million people worldwide are affected by diabetic retinopathy. Diabetic retinopathy is the leading cause of vision loss in adults of working age (20 to 65 years) in industrialized countries.
By 2025, the largest increases in diabetes prevalence will take place in developing countries. According to the International Diabetic Federation the number of individuals with diabetes will increase from 246 million at present to 380 million by 2025 (1). Due to an increasing prevalence of pre-diabetic dysglycaemia, a large number of individuals are at risk of developing T2DM particularly, due to genetic predisposition, life style and obesity (e.g. due to unhealthy diet and lack of exercise) (6).
The costs associated with the management of diabetes are 2-3 times higher than the management of other diseases, increasing from ˜US$2000 (patients without diabetes) to ˜US$6000 (patients with T2DM) per person. According to American Diabetes Association, in 2007, USA total direct costs associated with management of diabetes was ˜US$ 116 billion with a further ˜US$58 billion due to indirect costs (7).
T2DM is the sixth leading cause of death in Australia (1; 2; 4). According to Diabetes Australia, currently ˜900,000 Australians are diagnosed with T2DM (8). An estimated 275 Australians develop diabetes every day. The 2005 Australian AusDiab Follow-up Study (Australian Diabetes, Obesity and Lifestyle Study) showed that 1.7 million Australians have diabetes but that up to half of the cases of T2DM remain undiagnosed (9). By 2031 it is estimated that 3.3 million Australians will have T2DM (5). The total financial cost of T2DM is estimated at $10.3 billion per annum. Of this, career costs are estimated as $4.4 billion, productivity losses are $4.1 billion, health system costs are $1.1 billion and $1.1 billion is due to obesity (3). There is no doubt diabetes is a serious health crisis. Up to 60% of cases of T2DM can be prevented by good blood glucose control, and maintaining a healthy lifestyle can significantly improve the complications associated with diabetes.
Complications Associated with Type 2 Diabetes Mellitus:
Evolution of T2DM in patients can lead to elevated risk of (i) adverse cardiovascular events, associated with atherosclerosis, particularly coronary events, (ii) retinopathy, (iii) nephropathy and (iv) neuropathy. If not treated accordingly, T2DM can result in congestive heart failure, myocardial infarction, peripheral vascular disease, stroke, pancreatitis, end stage renal disease and blindness. An increasing body of evidence suggest that these complications arise mainly due to long term HYPERGLAECEMIA and HYPERTENSION leading to loss of nutritive blood flow and damage within these organs (10). Increasing body of evidence suggest that early and effective glucose control reduces the risk of these complications in T2DM (11). Moreover, occurrence of these complications, particularly myocardial infarction and congestive heart failure, directly correlated with the increased levels of glucose and hemoglobin A1c (HAc1) in patients with T2DM (12). Remarkably, perioperative tight glycaemic control also reduce post diabetes coronary artery bypass graft complications such as mortality, infections, length of hospital stay and others factors (13) indicating elevated glucose concentrations are detrimental in long term disease manifestations as well as acute interventions and surgery. Treatment of diabetes includes oral and injectable medicines each of which has its own benefits and risks associated with the disease.
Management of Type 2 Diabetes Mellitus:
Individuals with T2DM are often prescribed tablets to control their blood glucose levels. These tablets are intended to be used in conjunction with healthy eating and regular physical activity, not as a substitute. The aim of diabetes management is to keep blood glucose levels as close to ‘normal’ as possible, that is between 4 to 6 mmol/L (fasting), as this will help prevent both short-term and long-term diabetic complications. Regular blood glucose monitoring is necessary to see if the treatment being followed is adequately controlling blood glucose levels.
(i) Insulin Therapy:
Insulin, a biological medicine, is infused subcutaneously to patients to exogenously elevate insulin levels in the circulation, which results in lowering glucose concentrations. However, hypoglycaemic episodes are the most common complications occurring in insulin-treated patients (14). Improvement of glycaemic control with insulin results in weight gain (˜3.5 kg compared to conventional treatment at 0.4 kg), which in turn may contribute to an increased risk of cardiovascular disease and diabetes mortality (15).
(ii) Oral Treatments for T2DM:
Following tablets are currently being used for lowering blood glucose levels in T2DM. These include Biguanides, Sulphonylureas, Thiazolidinediones, Glitazones, Meglitinides, Alpha Glucosidase Inhibitor, incretin-based therapies or combinations thereof.
Although all of the agents mentioned above provide significant benefit imparted by improving glycaemic control and reducing complications, treatment with all of the agents is associated with adverse drug reactions, some of which can be serious and even life threatening. Thus, due to (i) hypoglycaemic risk in insulin and Sulphonylurea therapy, (ii) significant congestive heart failure and bone fracture episodes in thiazolidinediones, (iii) increased cardiovascular risk in rosiglitazone therapy, (iv) pancreatitis associated with Exenatide therapy, (v) lactic acidosis associated with Metformin therapy, and (vi) hypersensitivity reactions associated with sitagliptin therapy, there is a need for safer and/or more efficacious glucose lowering treatments, with improved risk-benefit profiles, to intervene with debilitating T2DM complications.
Alternative approaches to treatment of T2DM, such as for example combination therapies with dietary fiber, have also been reported. Indigestible dietary fibers, such as fructo-oligosaccharides (FOS), have long been thought to have beneficial effects on human health. To date four different clinical studies have shown contradicting results.
Effects of this class of neutraceutical in T2DM was first published in 1984 (16) demonstrating a slight reduction in blood fasting glucose levels (FGL) in patients with T2DM who were under Sulphonylurea treatment. This study showed that, in comparison to sucrose (G-F), intake of 8 gram per day for 14 days of FOS comprising a combination of Glucose-Fructose-Fructose (G-F-F), G-F-F-F and G-F-F-F-F structures, derived from treatment of sucrose with transfructosidase, resulted in ˜7.6% reduction of FGL, ˜7.8% reduction in total cholesterol and ˜10.4% reduction of LDL-cholesterol.
FGL, total cholesterol and LDL-cholesterol were measured at the beginning (day 0) and at the end of the study (day 14). In this study, out of 14 subjects, 4 subjects showed elevated FGL whereas 10 subjects showed decreased FGL upon intake of FOS. Overall the authors suggested that the combination of FOS lower FGL in diabetic patients despite the fact that this study had (i) very minor FGL lowering effect (0.8 mmol/L reduction) (ii) increased FGL in 28.6% of the subjects (4 out of 14) and (iii) diabetic subjects with very high and uncontrolled glucose and lipid concentrations. Additionally, the study had (iv) limited scope (v) short duration (vi) and utilized several different short chain structures of FOS.
Another clinical trial (17) was conducted in 1999 on 20 T2DM patients who consumed 15 grams/day of FOS (composed of 95% FOS with degree of polymerization of 3 to 10) for 20 days. The patients were under glucose lowering medications (exact medication is unknown), anti-hypertension agents and lipid-lowering drugs. Blood was collected at the beginning (day 1) and end (day 21) of the study. The authors reported that, in comparison to placebo (D-Glucose), no significant effect of FOS on FGL was found in these patients.
A further clinical trial was published (18) on 12 patients with T2DM who were either on sulfonyleurea and/or Metformin. The authors concluded that, in comparison to placebo sucrose (G-F), treatment of T2DM with 20 gram/day of FOS (44% G-F-F, 46% G-F-F-F and 10% G-F-F-F-F purchased from ACTILIGHT, France) for 28 days did not change the patient's FGL.
US patent application US2009/0214511 purports to describe an inulin-containing digestible formulation, which also includes as essential ingredients sucrose and an amylase enzyme, that is effective in “stabilizing and balancing” blood glucose in hyperglycemic, diabetic and/or pre-diabetic patients. It also states that taking 4 grams of the formulation each day “may” improve blood glucose control. Although this patent application refers to treatment of “30 patients” with this formulation, there is no information on either the diabetic state (or otherwise) of any of the “patients”, blood glucose levels of any of the patients, either before or after treatment with the formulation, or indeed any information on the type and quantity of any anti-diabetic medication that the patients may have been taking, if any was taken.
Despite the above discussed attempts to better T2DM treatment, there is still a need for alternative treatments, with more efficacious blood glucose level control and improved adverse reaction profile.
It is an objective of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art treatments, or to provide a useful alternative.